This is a proposal for the development of new reactions and strategies that are relevant to both chemical- and bio-synthesis. Each idea is inspired by the structure of a biologically active natural product. In nearly every case the design includes the use of one or more reactions (or reaction cascades) that introduces a large degree of molecular (structural) complexity into the product. In most cases these reactions have been identified following a critical, mechanistic analysis of the biosynthetic pathway by which the natural product has likely been made. In turn, this has led to the subtheme-common to Aims II-V-whereby we will attempt to exploit potentially 'spontaneous'biosynthetic events. The 'big picture'hypothesis is that organisms sometimes produce metabolites, by the collective action of ubiquitous classes of enzymes (e.g., those commonly producing polyketides and terpenes), that just happen to be endowed with sufficient reactivity that they subsequently undergo a spontaneous (set of) reaction(s) that further, and often dramatically, alter their chemical structures. These final 'polishing'steps can reveal much new chemistry and they provide structures that are, presumably, of evolutionary advantage to the organism. To the extent our mechanism-based, specific hypotheses are proven to be correct, then some remarkable new chemical reactions, having the potential to introduce substantial levels of structural complexity, will be discovered. Aim I. Develop a highly efficient, second generation total synthesis of the natural product, oocydin A (aka haterumalide NA, la). Develop a novel transannular cyclization of an allylic silane to a maleimide to efficiently produce the unique skeletal architecture in the alkaloid leuconolam (Ib). Aim II. Are spontaneous singlet oxygen reactions and an endoperoxide metathesis responsible for the production of the new peroxidic, antimalarial agent II, whose structure we have recently deduced? Aim III. Exploit spontaneous intramolecular Diels-Alder (IMDA) reactivity in the context of synthesis of octalinoyltetramic acid natural products Illa-llle. Test our hypothesis that a pyrylium ion is the active dienophile in a spontaneous bimolecular Diels-Alder reaction that forms methyl sarcophytoate (Illf). Aim IV. Do spontaneous hetero-Diels-Alder, electrocyclic, oxidation, and Claisen reactions interlink nearly all members of the penostatin family (IV-A-I)? Aim V. Do spontaneous electron transfer, radical macrocyclization, oxygenation, hydrogen atom transfer, elimination, and Diels-Alder events lead to hirsutellones A-F (V-A-F) (and GKKs and pyrrocidines)?